Cell death after traumatic brain injury (TBI) evolves over days to weeks. Despite advances in understanding biochemical mechanisms that contribute to posttraumatic brain cell death, the time course of cell injury, death, and removal remains incompletely characterized in experimental TBI models. In a mouse controlled cortical impact (CCI) model, plasmalemma permeability to propidium iodide (PI) was an early and persistent feature of posttraumatic cellular injury in cortex and hippocampus. In cortical and hippocampal brain regions known to be vulnerable to traumatic cell death, the number of PI + cells peaked early after CCI, and increased with increasing injury severity in hippocampus but not cortex (P < 0.05). Propidium iodide labeling correlated strongly with hematoxylin and eosin staining in injured cells (r = 0.99, P < 0.001), suggesting that plasmalemma damage portends fatal cellular injury. Using PI pulse labeling to identify and follow the fate of a cohort of injured cells, we found that many PI + cells recovered plasmalemma integrity by 24 h and were terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling negative, but nonetheless disappeared from injured brain by 7 days. Propidium iodide-positive cells in dentate gyrus showed significant ultrastructural damage, including plasmalemma and nuclear membrane damage or overt membrane loss, in all cells when examined by laser capture microdissection and transmission electron microscopy 1 to 24 h after CCI. The data suggest that plasmalemma damage is a fundamental marker of cellular injury after CCI; some injured cells might have an extended window for potential rescue by neuroprotective strategies.

Background: Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genomewide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity.

Purpose of the review Hemoglobin (Hb) and its scavenger proteins haptoglobin (Hp) and hemopexin (Hx) associate with HDL and influence the inflammatory properties of HDL. Moreover, HDL from Hx-null mice is proinflammatory. In addition, Hx deficiency is implicated in a number of other inflammatory diseases such as septic shock and experimental autoimmune encephalomyelitis. This review highlights studies that demonstrate novel insights into the physiological protective role of hemopexin in inflammatory diseases. Recent findings Recent studies demonstrate that Hx-dependent uptake of extracellular heme leads to the de-activation of Bach1 repression leading to the transcriptional activation of anti-oxidant HO-1 gene. Levels of circulating Hx have been implicated in the prognosis for patients with septic shock. In addition, Hx therapy has been shown to be beneficial in cardiovascular disease, cerebral ischemic injury and experimental autoimmune encephalomyelitis. Summary These studies suggest that heme scavenging is a major mechanism by which Hx defends against oxidative stress and related inflammatory disorders. Hx therapy may provide a novel protective role against heme and oxidative stress mediated inflammatory conditions including atherosclerosis.

Recent studies have examined the influence on patterns of human genetic variation of a variety of cultural practices. In India, centuries-old marriage customs have introduced extensive social structuring into the contemporary population, potentially with significant consequences for genetic variation. Social stratification in India is evident as social classes that are defined by endogamous groups known as castes. Within a caste, there exist endogamous groups known as gols (marriage circles), each of which comprises a small number of exogamous gotra (lineages). Thus, while consanguinity is strictly avoided and some randomness in mate selection occurs within the gol, gene flow is limited with populations outside the gol. Gujarati Patels practice this form of “exogamic endogamy.” We have analyzed genetic variation in one such group of Gujarati Patels, the Chha Gaam Patels (CGP), who comprise individuals from six villages. Population structure analysis of 1,200 autosomal loci offers support for the existence of distinctive multilocus genotypes in the CGP with respect to both non-Gujaratis and other Gujaratis, and indicates that CGP individuals are genetically very similar. Analysis of Y-chromosomal and mitochondrial haplotypes provides support for both patrilocal and patrilineal practices within the gol, and a low-level of female gene flow into the gol. Our study illustrates how the practice of gol endogamy has introduced fine-scale genetic structure into the population of India, and contributes more generally to an understanding of the way in which marriage practices affect patterns of genetic variation.

Objective We previously reported that Hemopexin (Hx), a heme scavenger, is significantly increased and associated with proinflammatory HDL under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating oxidative damage, the role of Hx in the development of atherosclerosis is unknown. Approach and Results We used Hx and apoE double knockout mice (HxE−/−) to determine the role of Hx in the development of atherosclerosis. HxE−/− mice had significantly more free heme, ROS, and proinflammatory HDL in their circulation, when compared to control apoE−/− mice. Atherosclerotic plaque area (apoE−/− = 9.72 ± 2.5 x104 μm2 and HxE−/− = 27.23 ± 3.6 x104 μm2) and macrophage infiltration (apoE−/− = 38.8 ± 5.8 x103 um2 μm2 and HxE−/− = 103.4 ± 17.8 x103 μm2) in the aortic sinus were significantly higher in the HxE−/− mice. Atherosclerotic lesions in the aortas were significantly higher in the HxE−/− mice compared to apoE−/− mice. Analysis of polarization revealed that macrophages from HxE−/− mice were more M1-like. Ex vivo studies demonstrated that HxE−/− macrophage cholesterol efflux capacity was significantly reduced when compared to apoE−/− mice. Injection of human Hx (hHx) into HxE−/− mice reduced circulating heme levels and hHx pretreatment of naïve bone marrow cells ex vivo resulted in a shift from M1-like to M2-like macrophages. Conclusion We conclude that Hx plays a novel protective role in alleviating heme induced oxidative stress, improving inflammatory properties of HDL, macrophage phenotype and function, and inhibiting the development of atherosclerosis in apoE−/− mice.